IE44320B1

IE44320B1 - Esters of steroid 17-ds having a depot action

Info

Publication number: IE44320B1
Application number: IE2738/76A
Authority: IE
Original assignee: Schering Ag
Priority date: 1975-12-19
Filing date: 1976-12-15
Publication date: 1981-10-21
Also published as: FI57263C; YU293176A; HU179343B; NO145620B; NO145620C; FR2335231B1; PH13907A; PT65973B; DD132270A5; US4119626A; SE428930B; IL50981A0; DK566076A; NO147717C; DK146629C; BE849553A; FR2335231A1; FI763544A; IT1065783B; ES454297A1

Abstract

Steroid esters of the Formula I I wherein the A, B, C, and D rings can be substituted in the usual manner, R10 is hydrogen or methyl; R13 is alkyl of 1-3 carbon atoms; R17 is 17 alpha -alkynyl or alkadiinyl of up to 4 carbon atoms or 17 beta -acetyl, Z is X-OH, Y-CO-OH, X-O-CO-Y-CO-OH, X-O-CO-R, Y-CO-OR, X-O-CO-Y-CO-OR, or X-O-SO2-R; X is a straight-chain or branched alkylene of 1-6 carbon atoms, optionally interrupted by O or S atoms, wherein the chain or branches can be substituted by -OH, -O-CO-R, or -O-SO2-R; Y is a direct bond, a straight-chain or branched carbon chain of 1-3 atoms, optionally interrupted by an O or S atom if Y is linked to the steroid residue via -O-CO-; of 1-16 atoms if Y is linked to X via -O-CO; or 1,4-phenylene, 1,4-cyclohexylene, or 1,3-cyclopentylene optionally substituted by alkyl of 1-2 carbon atoms, or groups analogously 1,2- and 1,3-disubstituted, respectively; and R is an optionally substituted alkyl of up to 22 carbon atoms, have longer acting activity than the corresponding unesterified steroids and higher activity than the corresponding long chain esters.

Description

This invention relates to steroid esters having a depot action.

We have nov; found that a steroid in which the 17-position is substituted by i) an alkynyl or chlorine-substituted alkynyl radical in the a-position or an acetyl or fluorine-substituted acetyl radical in the β-position, and by iii a group of the general formula —0—CO—Z in which Z represents X—OH, X—0—CQ—Y—CO—OH, X—0—CO—R, X—0—CO—Y—CO—OR or X—0—S02—R, in which X represents a saturated bivalent hydrocarbon radical having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and may be unsubstituted or substituted by one or more of the same or different substituents selected from —OH, —-OCOR and —0S02R groups, Y represents a direct bond, a bivalent aliphatic radical which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and which has from 1 to 16 carbon atoms, or a cyclohexylene, cyclopentylene or phenylene group which may be unsubstituted or substituted by one or more of the same or different substituents selected from methyl and ethyl groups, and R represents a hydrocarbon or heterocyclic radical which may be unsubstituted or substituted and which has in total up to 22 carbon atoms, and its physiologically tolerable salts, have a depot effect. - 2 Accordingly, the present invention provides such a compound and a salt, especially a physiologically tolerable salt, of such a compound.

The remainder of the steroid molecule may be unsubstituted or substituted, saturated or unsaturated, provided biological activity is maintained.

The steroid may contain a 10-methyl group, or such a group may be absent; it may contain a 13-methyl.,-ethy 1, -propyl or -isopropyl group.

A chlorine-substituted alkynyl radical in the 17a-position may, for example, be chloroethynyl; a fluorine-substituted acetyl radical in the 17B-position may be, for example, FH2C—CO—.

A hydrocarbon or heterocyclic radical represented by R may be unsubstituted or substituted, the total number of carbon atoms therein being up to 22. For example, a hydrocarbon radical may, if desired, be interrupted by one or more of the same or different atoms selected from oxygen and sulphur.

The saturated radical represented by X contains non-cyclic and/or cyclic groups, and is usually straight or branched alkylene.

The aliphatic radical represented by Y may be unsaturated or saturated, but is usually saturated.

Thus, this invention especially provides an ester of the general formula - 3 44320 in which the rings A, B, C and D may be unsubstituted or substituted, and may be saturated or unsaturated, R10 represents a hydrogen atom or a methyl group, Rj3 represents an alkyl group having from 1 to 3 carbon atoms, R17 represents an alkynyl group in the 17a-position or an acetyl group in the 17e-position, and Z represents X—OH, X—0—CO—Y—CO—OK, X—0—CO—R, X—0—CO—Y—CO—OR, or X—0—SO?R in which X represents a straight or branched alkylene group having from 1 to 6 carbon atoms, optionally interrupted by one or more 0- or S-atoms, which may, if desired, be substituted by—OH, —0—CO—R or —0—SO2—R, Y represents a direct bond, a straight of branched carbon chain optionally interrupted by one or more 0- or S-atoms, the chain having from 1 to 16 carbon atoms, or a 1,4-phenylene, 1,4-cyclohexylene or 1,3-cyclopentylene group or an analogous 1,2- or 1,3disubstituted group, which may be unsubstituted or substituted by an alkyl group having 1 or 2 carbon atoms, and the or each R represents an unsubstituted or substituted hydrocarbon or heterocyclic radical having up to 22 carbon atoms, and a salt, especially a physiologically tolerable salt, thereof.

The steroid molecule may be further substituted in conventional manner. As possible substituents there may be mentioned, for example, - 4 *432o etherified and esterified 2-, 4-, 6-, 7- and/or 16-positions, methylene groups in the 1,2-, 6,7and/or 15,16;positions, halogen atoms, preferably a fluorine or chlorine atom, in the 2-, 4-, 6-, 7-, 9-, 11- and/or 16-positions.

The rings A, B, C and D may be saturated or unsaturated, and double bonds may be present, for example, in the 1(2)-, 3(4)-, 4(5)-, 5(10)-, (6)-, 6(7)-, 9(10)-, 9(11)-, 11(12)- and/or 15(16)-positions.

An alkynyl radical in the 17a-position is preferably a lower alkynyl radical and may contain one or more triple bonds. For example, it may be an ethynyl, chlorethynyl, propynyl or butadiynyl group, ethynyl being preferred.

The radical represented by X is especially a straight or branched alkylene group having from 1 to 6 carbon atoms and optionally interrupted by one or more 0- or S-atoms, or a cycloalkylene group having up to 6 carbon atoms, the chain or ring being unsubstituted or substituted by an —OH, —0—CO—R or —0—SO2R group at any place in the chain or ring, but preferably terminally i.e. to give a —CH2OH, —CH2— 0—CO—R or —CH2—0—S02—R group. For X there may be mentioned, for example, the following groups: —ch2—, —CH2—ch2—, ch3r2- 5 44320 CH3 CH3 ch3 I ! S —C— , —CH2—CH—CH2—- and —Ch—CH3—CH2— ch3 chains having from 1 to 3 atoms being preferred.

The radical represented by Y is especially a direct carbon-to carbon bond, a straight or branched carbon chain of 1 to 3 atoms optionally inter5 rupted by an 0- or S-atom such, for example, as ch3 —CH2—, -7-CH2—CH2—— , —"CH—CH2—, CH3 ! —CH2—CH—, —CH2—CH2—CH2—, —CHZ—0—CH2— or —CH2—S—CH2— or a 1,4-phenylene, 1,4-cyclohexylene or 1,3-cyclopentylene group, which may be unsubstituted or substituted by an alkyl group having 1 or 2 carbon atoms. Y may also represent a carbon chain having from 1 to 16 carbon atoms, optionally interrupted by one or more 0- or S-atoms.

The monovalent radical represented by R may contain one or more aliphatic, cycloaliphatic, aromatic or heterocyclic groupings and may there15 fore belong, for example, to the aliphatic, cyclo-aliphatic, aromatic, aromatic-aliphatic or heterocyclic series. The radical may be saturated or unsaturated, unsubstituted or substituted, for example in a conventional manner. As examples of substituents there may be mentioned alkoxy, oxo and amino groups and halogen atoms. R may contain up to 22 carbon atoms, and preferably from 4 to 18 carbon atoms. - 6 As possible radicals represented by R there may be mentioned, for example : alkyl and substituted alkyl groups such, for example, as the methyl, diethylaminomethyl, chloromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, pentyl, isopentyl, tert.-pentyl, 2-methyl butyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, pentadecyl, hexadecyl and octadecyl group, cycloalkyl and cylcoalkylalkyl groups such, for example, as the eyclopentyl, cyclohexyl and cyclopentylmethyl group, aryl and aralkyl groups such, for example, as the phenyl, benzyl, 2-phenethyl, tolyl, cinnamyl, a- or β-naphthyl group, heterocyclic and heterocyclic-containing groups such, for example, as the pyridyl, piperidyl, pyrrolidinyl, furanyl, piperidinomethyl and morpholinomethyl group, and hydrocarbon groups interrupted by one or more oxygen atoms such, for example, as the 9-methyl-2,5,8-trioxadecyl group.* Preferred depot-steroid esters are compounds of the general formula *thus COR may be 10-methyl-3,6,9-trioxa-undecanoyl i.e. C0CH20CH2CH20CH2CH20CH(CH 3)z. - 7 4 4 3 2 0 in which R13 and Z have the meanings given above, the broken lines represent optional further carbon-to-carbon bonds, A represents, together with adjacent carbon atoms of the B ring, the grouping and the C ring contains a double bond in the Π,12-position shown, i.e. the A, B and C rings are or A represents, together with adjacent carbon atoms of the B ring, the grouping Rio and the C ring is saturated, and R10 represents a hydrogen atom or a methyl group, R3 represents a hydrogen atom, a (03—C6)-acyl, (Cj—C6)-alkylsulphonyl, (C3—C5)-alkyl or (C3—C8)-cycloalkyl group, T5 W = H2, 0 or H, 0R3 represents a double bond in the 4,5-, 5,6- or 5,10-position, and - 8 R15 and Rjg each represent a hydrogen atom or both together represent a methylene group in the a- or β-position or a further carbon-tocarbon bond between the carbon atoms C15 and Cjg, Preferred lower acyl groups R3 are the acetyl, propionyl and butyryl 5 groups. Suitable alkyl groups and alkyl moieties in alkylsulphonyl groups are lower alkyl groups and moieties, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert.-butyl. Suitable cycloalkyl groups are those having from 3 to 8 carbon atoms, the cyclopentyl group being preferred.

Other preferred depot-steroid esters are compounds of the general formula H3 in which R10, R13 and Z have the meanings given above, R3 and R2 each represent a hydrogen atom or both together represent a methylene group or a further carbon-to-carbon bond between the carbon atoms C3 and C2, Ri, represents a hydrogen or a chlorine atom, - 9 <4320 Rs represents a hydrogen atom, a chlorine atom or a methyl group and — 7 represents a single or double bond between the carbon atoms C6 and C7. 17β -(0- Propionylglycolloyloxy) - 17a - ethynyl - 18 - methyl 5 15«,16a- and 15β,16β - methylene - 4 - oestren - 3 - one should also be mentioned.

The depot-steroid esters of the invention generally produce higher levels of active substance than do the hitherto known steroid esters. The increase may be up to 800%. The steroid esters of the present invention generally possess the same pharmacological properties as the known corresponding steroid alcohols from which they may be prepared. They are especially distinguished by their strong oestrogenic or gestagenic activities.

It is known that a protracting effect can be produced when biologically active steroid alcohols are esterified with long chained, branched or cyclic fatty acids, or biologically active lower esters of steroid alcohols are converted into higher esters.

The length or the branching of the fatty acid is a decisive factor for the desired protracting effect. Thus, for example, a considerable protracting effect may be achieved with an undecyTate, but owing to the strongly decreased splitting of the steroid ester liberated from the depot a considerably decreased action has to be taken into account. As the hydrolysis of a tertiary ester, as compared with the metabolisation or direct separation of the ester, proceeds very slowly, it is necessary to administer doses of the long-chained ester that are unsuitably high in order to achieve the therapeuti c effect of the alcohol. - 10 44320 We have found that a depot-steroid ester of the invention may be hydrolysed either completely or almost completely and yields correspondingly high levels of active substance, and that the speed of hydrolysis and therewith the duration of action can be controlled by the choice of the radicals X, Y and R irt the general formulae I, II and III.

Whereas, usually, after esterification of the tertiary 17-hydroxyl group, receptor-binding of the steroid no longer occurs in in vitro tests, in the case of a 17-hydroxy-ester (Z=X—OH) of the invention, for example, the 17-glycollate, there is observed, as compared with the steroid alcohol, a receptor-binding that is decreased to a small extent, e.g. only by a factor of 3 to 4. In this way the desired therapeutic effect may be strengthened, because a pharmacologically active compound is present prior to the splitting of the hydroxy-ester.

The length and structure, especially of the second and optionally the third, ester residue in a compound of the general formula I is a determining factor for the duration of action. By the esterification of a 17-OH steroid with a hydroxy- or carboxy-carboxylic acid solubility is increased and in many cases the melting point is simultaneously raised. Thereby a few of the new depot-esters may be administered intramuscularly either in oily solution or in aqueous microcrystalline suspension.

The present invention also provides a process for the preparation of a depot-ester of the general formula I or a salt thereof, which comprises esterifying the 17-hydroxy group in a pharmacologically active 17-hydroxy steroid having an unsubstituted alkynyl or chlorine-substituted alkynyl radical in the 17ot-position or an unsubstituted acetyl or fluorine-substi - 11 44330 tuted acetyl radical in the 17e-position. Preferably a steroid alcohol of the general fonnula in which A, B, C and D, Rlo, R13 and r17 have the meanings given above 5 is esterified.

The esterification may be carried out by a method known per se. For example, the tertiary depot-ester may be formed by esterificationuith a short-chained hydroxy-carboxylic acid of the general formula HO—X—COOH to form a hydroxy-carboxylic acid ester of the general formula Q—0—CO— X—OH (V) where Q represents the steroid residue and X has the meaning given above. The hydroxy-carboxylic acid ester (V) may then be further esterified with a further carboxylic acid of the formula R—COOH, a dicarboxylic acid of the formula HOOC—Y—COOH or sulphonic acid of the formula R—SO2OH to give a compound of the general formula T5 Q—0—CO—X—0—CO—R (VI), Q—0—CO—X—0—CO—Y—COOH (VII) or Q—0—CO—X—0—SO2R (VIII) where Q, X, Y and R have the meanings given above. Esterification of the acid of the general formula VII with an alcohol of the general formula ROH leads to a compound of the general formula - 12 Q—0—CO—X—Ο—CO—Υ—COOR (IX), Q, X, Y and R having the meanings given above. Alternatively, esterification of the compound of the general formula IV with the desired acylated hydroxy-carboxylic acid of the general formula HOOC—X—0—COR or esterification of the compound of the general formula V with a semi-esterified carboxy-carboxylic acid of the general formula HOOC—Y—COOR, gives a product of the general formula VI or IX respectively. In this way there are obtained compounds that contain one, two or three ester groups.

Thus, the steroid alcohol IV may be dissolved in an inert solvent and reacted with the desired acid anhydride or halide in the presence of an acid or basic catalyst suitably at a temperature in the range of from 0 to 150°C.. A further possibility consists in reacting the steroid alcohol IV with the free hydroxy-carboxylic acid HOOC—X—OH or one that is esterified at the hydroxyl group HOOC—X—0—COR suitably by treatment with trifluoroacetic anhydride in an inert solvent optionally with the addition of an acid catalyst suitably at a temperature in the range of from 0 to 40°C.

Suitable acid catalysts are for example, para-toluene sulphonic acid, perchloric acid and sulphuric acid; suitable basic catalysts, which may also serve as solvents, are, for example, triethylamine, pyridine and collidine. Any inert solvent may be used as the reaction medium, preferably benzene or a solvent derived from benzene, e.g. toluene or chlorobenzene, or an ether, e.g. diethyl ether, dioxan or tetrahydrofuran, a hydrocarbon, e.g. hexane, a halogenated hydrocarbon, e.g. methylene chloride, ethylene chloride or chloroform, or a polar solvent, e.g. acetonitrile or dimethyl sulphoxide. - 13 44320 A hydroxy-ester V {Z = XOH) obtained with a hydroxy-fatty aeid may be esterified at the free hydroxyl group in the manner usual for primary alcohols. A preferred esterifying agent is an acid anhydride or haTide in the presence of a basic catalyst. The reaction temperature is suitably in the range of from 0 to 100°C. The hydroxy-fatty acid may contain 1 to 3, preferably 1, hydroxyl group.

An acyloxy-fatty acid ester VI (Z = X—0—CO—R) thus obtained or obtained with an acyloxy-fatty acid may be hydrolysed with a catalytic quantity of a solution of an alkali Or alkaline earth metal hydroxide in alcohol at a low temperature, suitably in the range of from 0 to 50°C and a short reaction time, suitably of from one minute to 3 hours. The reaction mixture may also contain an inert solvent or diluent, e.g. methylene chloride, diethyl ether or tetrahydrofuran. After the hydrolysis, if desired esterification in the second stage may be carried out with the desired carboxylic or sulphonic acid (R—COOH or R—SO2OH) or dicarboxylic acid (HOOC—Y—COOH).

It is often advantageous to prepare first in one step a hydroxy-ester esterified with a lower fatty acid, then to hydrolyse to form the free hydroxy-ester, and only in the last step to esterify with the acid of the desired chain length.

A 17-glycollic acid ester may also be prepared, for example, in the following manner: A 17-crotonic acid ester is first prepared with crotonic acid in the presence of trifluoroacetic anhydride. After the protection of optionally present ketone groups, for example in the 3- or 3,20-position, preferably - 14 4432ο by ketalisation, oxidation is carried out with potassium permanganate in the presence of formic acid at a temperature around the freezing point of water to form the 2,3-dihydroxybutyric acid ester. By oxidative splitting with periodate at a temperature from 0 to 50°C, the 17-glyoxalic acid ester is obtained, which by reduction is changed in the desired glycollic acid ester. The oxidation with permanganate and the oxidative splitting with periodate are carried out in aqueous inert solvents, such, for example, as acetone, tetrahydrofuran or dioxan. The reduction may be carried out in the usual manner with an alkali metal boronate or lithium tri-tert.10 butoxy-alanate. Depending on the desired end product, optionally present protected keto groups may be liberated directly or after esterification of the hydroxyl group of the glycollic acid ester.

This invention also provides a pharmaceutical preparation, especially a depot-preparation, which comprises a steroid ester of the general formula I or a physiologically tolerable salt thereof, in admixture or conjunction with a pharmaceutically suitable carrier. Suitably the preparation is in dosage unit form.

The gestagenically or oestrogenically active steroid esters are suitable, for example, for the control of fertility in human beings and animals (especially as a contraceptive) or for the treatment of menopausal complaints in women. There may also be used combinations of, for example, gestagenic and oestrogneic or oestrogenic and androgenic steroid esters.

The effective dose depends on the purpose of the treatment, the nature of the active, substance and the desired duration of action. The effective dose of, for example, 17a - ethynyl - 18 - methyl - 17g -(0- undecanoyl - 15 44320 glycol!oyloxy) - 4 - oestren - 3 - one for the control of fertility in women is thought to be from 10 to 50 mg for 3 months and the quantity of other gestagenically active steroid esters administered is the same as that which corresponds, to the administration of 3-manthlv 10 to 50 mg of 17a - ethynyl - 18 - methyl - 170 -(0- undecanoyl - glycolloyloxy) - 4 oestren - 3 - one.

A preparation of the present invention may be administered perorally or by implantation or injected subcutaneously or injected intramuscularly in oily solution or in aqueous crystal suspension. The injection volume is, for example, from 1 to 4, preferably 1 to 2 ml.

For preparing an oily solution the steroid ester may be dissolved in a solvent or solvent mixture suitable for the injection, filtered sterile and charged into ampoules under aseptic conditions.

Suitable oily solvents are, for example, sesame oil and castor oil.

For increasing the solubility of the active substance, solubilizers such, for example, as benzyl benzoate or benzyl alcohol, may be added to the oily solvent. Besides those already mentioned, there may be used other vegetable oils, e.g. linseed oil, cotton seed oil, sunflower oil, ground-nut oil, olive oil and wheat oil. Also suitable are synthetic oils, e.g. polyethylene glycol, triglycerides of higher saturated fatty acids and monoesters of higher fatty acids. As a solvent mixture, a mixture of castor oil/benzyl benzoate in the ratio of 6: 4 is preferred.

The following Examples illustrate the invention.

Example 1 To 30.9 grams of crotonic acid in 800 ml of benzene are added 48.1 ml - 15 *4320 of trifluoracetic anhydride, and the mixture is stirred for 30 minutes at room temperature. 50 Grams of 17a-ethynyl-17g-hydroxy-18-methyl-4-oestren3- one are then added and the whole is stirred for 30 minutes at room temperature. The reaction solution is diluted with ether, washed with water and sodium hydrogen carbonate solution, dried and evaporated. For enol-ester splitting the residue is taken up in 1.3 litres of methanol, 130 ml of sulphuric acid (8% by volume ) are added, and the whole is heated under reflux for 2 hours. After precipitation in ice-water, the precipitate is filtered off, washed with water, taken up in methylene chloride and dried. The residue obtained after evaporation is recrystallised from diisopropyl ether/acetone, and 43.3 grams of 17a-ethynyl-17e-crotonoyloxy-l8-methyl4- oestren-3-one melting at 187—188°C are obtained.

UV: (?ll= 18700; .-.,,, = 18100.

To 45 grams of 17a-ethynyl-17(j-crotonoyloxy-18-methyl -4-oestren-3one in 450 ml of methylene chloride are added 90 ml of ortho-formic acid triethyl ester, 112 grams of 2,2-dimethyl-l,3-propandiol and 450 mg of para-toluene sulphonic acid, and the whole is stirred for 60 minutes at a bath temperature of 50°C. The mixture is then diluted with ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated. The residue is chromatographed over silica gel, and 39.5 grams of 17a- ethynyl - Ι7β - crotonoyloxy - 3,3 - (2,2 - dimethyltrimethylenedioxy)18 - methyl - 5 - and 5(10)-oestrene are obtained in the form of an oil.

Grams of 17a - ethynyl - 17β - crotonoyloxy - 3,3 - (2,2 - dimethyltrimethylenedioxy) - 18 - methyl - 5 - and 5(10)-oestrene are dissolved in 1.5 litres of acetone, the solution is cooled in an ice bath, 11.2 ml of - 17 44330 formic acid of 100% strength are added, and in the course of 2 hours a solution of 23.7 grams of potassium permanganate in 395 ml of water and 3.3 litres of acetone is added. The mixture is then further stirred for 30 minutes at 0°C, 1 litre of methylene chloride is added and precipitated pyrolusite is filtered off. The filtrate is concentrated to a great extent in vacuo, the residue is taken up in ether and the mixture is washed with water, dried and evaporated. By chromatography over silica gel there are obtained, in addition to T2 grams of unreacted starting material, 30.2 grams of 17a - ethynyl - 17g -(2,3 - dihydroxybutyryloxy) - 3,3 - (2,2 dimethyltrimethylenedioxy) - 18 - methyl - 5 - and 5(10)-oestrene in the form of an oil.

To 30 grams of 17a-ethynyl-170-(2,3-dihydroxy-butyroxy)-3,3-(252-dimethyltrimethylenedioxy)-18-methyl-5- and 5(10)-oestrene in 1.5 litres of dioxan are added 89.6 grams of sodium periodate in 450 ml of water, and the mixture is stirred for one hour at room temperature. The mixture is then stirred into ice-water, extracted with methylene chloride, washed with water and dried. By evaporation 28.5 grams of crude 17a - ethynyl - 3,3(2,2 - dimethyl - trimethylenedioxy) - 17β - glyoxyloyloxy - 18 - methyl5 - and 5(10)-oestrene are obtained.

To 32.5 grams of crude 17a-ethynyl-3,3-(2,2-dimethyltrimethylenedioxy)17g-glyoxyloyloxy-18-methyl-5- and 5(10)-oestrene in 995 ml of methanol and 142.5 ml of water are added in portions while cooling with ice 6.5 grams of sodium boranate. The mixture is then stirred for 10 minutes at ice bath temperature and stirred into ice-water. The precipitate phase acidified with 2N sulphuric acid is extracted with ether, washed with water and - 18 4432ο dried. The residue obtained after evaporation is chromatographed over silica gel, and 30.5 grams of 17a-ethyny1-3,3-(2,2-dimethyl-trimethylenedioxy)-17e-glycolloyloxy-18-methyl-5- and 5(10-oestrene are obtained. A test portion recrystallised from di isopropyl ether melts at 215.5—219°C. 200 mg of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-17i3-g1ycolloyloxy-18-methyl-5- and 5(10)oestrene in 2 ml of pyridine are allowed to stand with 1 ml of propionic anhydride for 3 hours at room temperature. The mixture is then stirred in ice-water, the precipitate is filtered off, taken up in ether, washed with water and sodium hydrogen carbonate solution and dried. By evaporation 240 mg of crude 17a - ethynyl - 3,3 - (2,2dimethyl - trimethylenedioxy) - 18 - methyl - 17B -(0- propionylglycolloyloxy) - 5 - and 5(10)-oestrene are obtained. 240 mg of crude 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy )-18methyl-17B-(0-propionyl-glycolloyloxy)-5- and 5(10)-oestrene in 6 ml of methanol and 1.2 ml of water are heated under reflux for one hour with 120 mg of oxalic acid. The mixture is diluted with ether, washed with water and dried. After evaporation the residue is chromatographed over silica gel, and by recrystallisation from diisopropyl ether 100 mg of 17a-ethynyl18-methyl-17B-(0-propionyl-glycolloyloxy)-4-oestren-3-one melting at 125— 126°C are obtained.

UV: e2uo = 17500.

Example 2 4.0 Grams of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-17Bglycol1oyloxy-18-methyl-5- and 5(10)-oestrene in 12 ml of pyridine and 8 ml of oenanthic anhydride are allowed to stand for 20 hours at room tempera- 19 ture. The mixture is then distilled with steam, and the residue is taken up in methylene chloride and dried. After evaporation, chromatography over silica gel is carried out, and 3.8 grams of 17a - ethynyl - 3,3 - {2,2dimethyl - trimethylenedioxy) - 17(3 - (0 - heptanoyl glycol! oyl oxy) - 18 5 methyl - 5 - and 5{10)-oestrene are obtained. 3.8 Grams of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-17B(0-heptanbylglycanoyloxy)-18-raethyl-5- and 5(10)-oestrene in 95 ml of methanol and 19 ml of vrater are heated under reflux with 1.9 grams of oxalic acid for 90 minutes. The mixture is then stirred into ice-water, the precipitate is filtered off, taken up in ether, washed with water and dried. After evaporation, chromatography over silica gel is carried out, and there are obtained 2.0 grams of 17a-ethynyl-17B-(0-heptanoy1-glyco11oyloxy)-18methyl-4-oestren-3-one melting at 90—91 °C.

UV: e201t = 17000.

Example 3 To 4.0 grams of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)17e-glycolloyloxy-18rmethyl-5- and 5(10)-oestrene in 12 ml of pyridine are added at ice bath temperature 4 ml of undecanoic acid chloride, and the mixture is allowed to stand for 20 hours at room temperature. By working up and purifying in a manner analogous to that in Example 2 3.9 grams of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-18-methyl-17g(0-undecanoyl-glycolloyloxy)-5- and 5(10)-oestrene are obtained. 3.9 Grams of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-18methyl-170-(O-undecanoyl-glycolloyloxy)-5- and 5(10)-oestrene in 95 ml of methanol and 19.5 ml of water are heated under reflux with 1.95 grams of - 20 oxalic acid for 90 minutes. By working up and purifying in a manner analogous to that in Example 2 there are obtained 2.0 grams of 17a-ethynyl 18-methyl-17g-(0-undecanoyl-glycol1oyloxy)-4-oestren-3-one as an oil.

UV: ε2ι,ο = 17000.

Example 4 1.3 Grams of 17a-ethynyl-3,3-(2,2-dimethyl-trimethylenedioxy)-17gglycolloyloxy-18-methyl-5- and 5(10)-oestrene in 39 ml of methanol are stirred with 3.9 ml of sulphuric acid of 8% strength by volume for 3 hours at room temperature. The mixture is then diluted with ether, washed with water and dried. After evaporation the residue is chromatographed over silica gel, and by recrystallisation from diisopropyl ether 620 mg of 17aethynyl-17B-glycolloyloxy-18-methyl-4-oestren-3-one melting at 158.5— 159.5°C are obtained.

UV: e2it0 = 17600.

Example 5 100 mg of 17a-ethynyl-17B-glycolloyloxy-18-methyl-4-oestren-3-one are dissolved in 1 ml of pyridine and 160 mg of 3-cyclopentyl-propionyl chloride are added while cooling. The mixture is allowed to stand for 24 hours at room temperature, stirred into ice-water, taken up with ether, washed neutral and chromatographed, after drying and concentrating, over silica gel. 110 mg of 17a-ethynyl-17e- {0-(3-cyclopentylpropionyl)-glycol1oyloxy}-18-methyl-4-oestren-3-one are obtained.

In a manner analogous to that in Example 5 there are prepared: 17ct-Ethynyl-17β-(O-tridecanoyl-glycol! oyl oxyj-4-oestren-3-one, 17a-ethynyl-l7β-(0-hexadecanoyl-glycol1oyloxy)-4-oestren-3-one, - 21 4433ο 17a-ethynyl-178-(0-octadecanoyl-glycolloyloxy)-4-oestren-3-one, 17a-Ethynyl-17 β-(0-tri decanoyl-glycol1oyloxy)-18-methyl-4-oestren3-one and 17a-ethynyl-178-(0-tridecanoyl-glycolloyloxy)-18-methyl-4,15-oestradien-3-one.

Example 6 500 mg of 17a-ethynyl-178-hydroxy’-18-methyl-4-oestren-3-one are dissolved in 5 ml of collidine (freshly distilled) and 180 mg of 4-dimethylaminopyridine and 1.25 grams of 2-nonanoyloxy-propionyl chloride are added while cooling with ice. The mixture is heated under nitrogen for 24 hours at 110°C. The reaction mixture is taken up with ether and washed neutral with an aqueous solution of oxalic acid and water. After drying the ether and concentrating in vacuo, chromatography over silica gel is carried out, and 17a-ethynyl-178-(2-nonanoyloxy-propionyloxy)-18-methyl-4-oestren3-one is obtained.

Example 7 (a) 1 Gram of 3-acetoxy-propionic acid are stirred in 21 ml of benzene with 1.05 ml of trifluoracetic anhydride for one hour at room temperature. While cooling and gassing with nitrogen 0.99 gram of 17a-ethynyV!7B-hydroxy-18-rnethyl-4-oestren-3-ane is added, and the mixture is stirred for 24 hours.

The reaction solution is decomposed with methanol/water and washed neutral with water, sodium hydrogen carbonate solution and again with water. The benzene solution is dried with sodium sulphate and concentrated in vacuo. The oily residue is chromatographed over silica gel, and 650 - 22 mg of 17B-(3-acetoxy-propionyloxy)-17a-ethynyl-18-methyl-4-oestren-3-one are obtained.

UV: e21f0 = 17200. (b) 250 mg of 17p-(3-acetoxy-propionyloxy)-17a-ethynyl-18-methyl4-oestren-3-one are dissolved in 2 ml of methylene chloride and 2 ml of methanol, and an ethanolic solution of potassium hydroxide is added at 5°C under nitrogen. After 2 hours the mixture is neutralized with glacial acetic acid and stirred into ice-water. The precipitated product is filtered off with suction and dried.

By chromatography over silica gel and recrystallisation from diisopropyl ether 200 mg of 17a-ethynyl-17f?-(3-hydroxypropionyloxy)18-methyl-4-oestren-3-one melting at 159—160°C are obtained.

UV: 62,,0 = 16400.

Example 8 mg of 17u-ethynyl-17g-glycolloyloxy-4-oestren-3-one are dissolved in 0.5 ml of dry pyridine and 0.11 gram of 3,6,9-trioxa-isododecanoyl chloride is added while cooling with ice. The whole is allowed to stand for 24 hours at room temperature under nitrogen, taken up in ether, washed with an aqueous solution of oxalic acid, the ether phase is dried and concentrated. By chromatography over silica gel there are obtained 64 mg of 17a-ethynyl-17g-(0-10-methyl-3,6,9-tri oxaundecanoyl-glycol1oy1oxy)-4oestren-3-one.

Example 9 Gram of 17a-ethynyl-17g-hydroxy-4-oestren-3-one is dissolved in 10 ml of collidine (freshly distilled) and 250 mg of 4-dimethylami no-pyridine - 23 are added. After cooling to +5°C, 0.65 ml of 0-acetylglycol1oyl chloride is added dropwise, and the whole is slowly heated to 100°C while gassing with nitrogen. After 1 hour the mixture is cooled, and a further 0.65 ml of acetoxy-glycoloyl chloride is added. The mixture is then heated for 3 hours at 100°C. After being cooled, the mixture is taken up in ether, washed neutral with oxalic acid solution and then with water, dried and evaporated. By chromatography over silica gel there are obtained 800 mg of 17e-(0-acetyl-glycolloyloxy)-17a-ethynyl-4-oestren-3-one melting at 179—180°C (from diisopropyl ether).

Example 10 500 mg of 17B-(0-acetylg1ycolloyloxy)-17a-ethynyl-4-oestren-3-one are dissolved in methylene chloride/methanol (1:1), the solution is cooled to 5°C. and an ethanolic solution of potassium hydroxide is added under nitrogen. After 15 minutes, the mixture is neutralised with acetic acid, stirred into ice-water and the precipitated product is filtered off with suction. By chromatography over silica gel 420 mg of 17a-ethynyl-17gglycolloyloxy-4-oestren-3-one melting at 207—210°C are obtained.

UV: E240 = 17000.

Example 11 100 mg of 17a-ethynyl-17g-hydroxy-4-oestren-3-one are dissolved in ml of dry pyridine, and, while cooling with ice and under nitrogen, 350 mg of 0-(4-octyloxybenzoyl)-glycoloyl chloride are added. The mixture is allowed to stand for 24 hours at room temperature, taken up with ether, washed with oxalic acid solution and water, and the ethereal phase is dried. - 24 By concentrating in vacuo and chromatography of the residue over silica gel 120 mg of 17a-ethynyl-17B-(0-(4-octyloxy-benzoyl)-glycolloyloxy}-4oestren-3-one are obtained.

Example 12 100 mg of 17a-ethynyl-17B-hydroxy-4-oestren-3-one are dissolved in ml of dry pyridine, and, while cooling with ice and under nitrogen, 0.5 ml of 0-{4-octyloxycarbonylcyclohexylcarbonyl)-glycolloyl chloride is added. After allowing the mixture to stand for 24 hours at room temperature, it is diluted with ether, washed with an aqueous solution of oxalic acid and then washed neutral with water. After drying the ether and concentrating in vacuo the residue is chromatographed over silica gel. 135 mg of 17aethynyl - 17b -(0-(4- octyl oxycarbonyl - cyelohexylcarbonyl} - glycolloyloxy) - 4 - oestren - 3 - one are obtained.

Example 13 To 10 ml of dimethyl sulphoxide are added 1.48 ml of diglycollic acid monomethyl ester and, while cooling, 1.5 ml of trifluoroacetic anhydride are added dropwise. After one hour 1 gram of 17a-ethynyl-17e-hydroxy4-oestren-3-one is added. The whole is allowed to stand for 24 hours under nitrogen at room temperature, poured into ice-water and extracted with ether. After drying and concentrating, chromatography over silica gel is carried out, and 430 mg of 17a-ethynyl-17B-(0-methoxycarbonylmethylglycolloyloxy)-4-oestren-3-one melting at 125—132°C (from diisopropyl ether) are obtained.

UV: e2i,o = 17200. - 25 44320 Example 14 100 mg of 17a-ethynyl-170-(O-methoxycarbonylmethyl-glyconoyloxy)4-oestren-3-one are dissolved in 1 ml of decanol, 5 mg of potassium tert.butylate are added, and the mixture is allowed to stand for one hour at room temperature. Acetic acid is added, the alcohol is removed in a high vacuum, and the residue is chromatographed over silica gel. 115 mg of 17a-ethynyl-178-(0-decyloxycarbonylmethyl-glycol1oyloxy)-4-oestren-3one are obtained.

Example 15 500 mg of 17a-ethyny1-17e-hydroxy-4-oestren-3-one are dissolved in 5 ml of freshly distilled collidine and, while cooling with ice and under nitrogen, 180 mg of 4-dimethylamino-pyridine and 2.1 grams of 4-undecanoyloxy-cyclohexanecarbonyl chloride are added. The mixture is heated for 3 hours at 100°C., after cooling and adding 2 ml of collidine a further 0.75 ml of the acid chloride is added, and the whole is heated for a further 6 hours at 100°C. After working up with ether and an aqueous solution of oxalic acid, drying and concentrating, 600 mg of crude substance remain behind. By chromatography over silica gel there are obtained 330 mg of 17a-ethynyl-170-(4-undecanoyloxy-cyclohexylcarbonyloxy)-4-oestren3-one.

Example 16 (a) 200 mg of 17a-ethynyl-17e-hydroxy-4-oestrene are dissolved in 2 ml of freshly distilled collidine and, while cooling with ice and gassing with nitrogen, 400 mg of acetoxy-glycolloyl chloride are added. The mixture is heated for 3 hours at 60°G, and, - 26 after cooling, there are added 200 mg of 4-dimethylami no-pyridine and a further 400 mg of the acid chloride. The reaction mixture is maintained at 60°C for a further 10 hours. After cooling, the mixture is diluted with ether, washed with an aqueous solution of oxalic acid and water, and the ether is dried. By chromatography over silica gel 170 mg of 17g-(0-acetyl-glycolloyloxy)17a-ethynyl-4-oestrene are obtained. (b) 50 mg of 17g-(0-acetyl-glycolloyloxy)-17a-ethynyl-4-oestrene are dissolved in 1 ml of methylene chloride and 0.5 ml of methanol, the mixture is cooled to 5°C, gassed with nitrogen and 0.5 ml of an ethanolic solution of potassium hydroxide of 3% strength is added. After 15 minutes the mixture is neutralised with acetic acid, taken up in ether and washed neutral. By chromatography over silica gel 35 mg of 17a-ethynyl-17B-glycolloyloxy4-oestrene are obtained.

Example 17 mg of 17a-ethynyl-17g-glycolloyloxy-4-oestrene are dissolved in 0.2 ml of dry pyridine and, while cooling, 100 mg of stearoyl chloride are added. The whole is allowed to stand for 24 hours. The mixture is then distilled with steam and the residue is taken up in ether, it is separated on analytical thin layer plates, the desired rapidly running product is rendered visible with primuline and eluted. 17 mg of 17erethynyl17g-(0-stearoyl-glycolloyloxy)-4-oestrene are obtained.

Example 18 500 mg of 17a-ethynyl-17g-hydroxy-5(10)-oestren-3-one are dissolved in 10 ml of freshly distilled collidine, and 250 mg of 4-dimethylamino- 27 44320 pyridine are added. After cooling to 5°C, 4 grams of O-undecanoyl-glycolloyl chloride are added and the whole is heated for one hour at 100°C. The mixture is cooled, ether and an ice-cooled aqueous solution of oxalic acid are added, washed neutral with water, the ethereal phase is dried and chromatographed with chlorine- and chloride-free methylene chloride over neutral silica gel washed with methanol. A mixture of 370 mg of 17a-ethynyl-17β-(O-undecanoyl-glycolIoyloxy)-5(10)-oestren-3-one and 17 aethynyl - 17β- (0 - undecanoyl - glycol!oyloxy) - 4 - oestren - 3 - one is obtained.

Example 19 500 mg of 17α-ethynyl-3-methoxy-1,3,5(10)-oestratrien-17e-ol are reacted in a manner analogous to that in Example 9 with acetoxy-glycolloyl chloride. 370 mg of 17β -(0- acetyl - glycolloyloxy) - 17a - ethynyl 3 - methoxy - 1,3,5(10) - oestratrien melting at 118—120°C. (from ethanol) are obtained.

Example 20 150 mg of 17$-(0-acetyl-glycolloyloxy)-17a-ethynyl-3-niethoxy-l,3,5(10)oestratriene are reacted in a manner analogous to that in Example 10 with ethanolic potassium hydroxide. 110 mg of 17a-ethynyl-17B-glycolloyloxy3-methoxy-l,3,5(10)-oestratriene melting at 133—135°C from diisopropyl ether) are obtained.

Example 21 mg of 17a-ethynyl-17B-glycolloyloxy-3-methoxy-l,3,5(10)-aestratriene are dissolved in 1 ml of dry pyridine and 120 mg of isovaleryl chloride are added. The mixture is allowed to stand for 24 hours, taken - 28 *433o up with an aqueous oxalic acid solution and ether, washed neutral with water, and the ethereal phase is dried and concentrated. By chromatography over analytical thin layer plates 55 mg of 17a-ethynyl-17@-(O-isovaleryl-glycolloyloxy)-3-methoxy-l,3,5{10)-oestratriene are obtained.

Example 22 500 mg of 17a-ethynyl-17g-hydroxy-l,3,5(10)-oestratrien-3-ol are dissolved in 5 ml of dry collidine, 180 mg of 4-dimethylami no-pyridine are added and, while cooling with ice and under nitrogen, 2.2 grams of 0-undecanoyl-glycolloyl chloride are added. The mixture is heated for 3 hours at 70°C, stirred into aqueous oxalic acid solution, taken up with ether, and agitated for 30 minutes with an excess of an aqueous solution of sodium hydrogen carbonate at 10°C. After washing, drying and concentrating the ethereal phase, chromatography over silica gel is carried out. 420 mg of 17a-ethynyl-17e-(0-undecanoyl-glycolloyloxy)-l,3,5(10)-oestratrien-3-ol are obtained.

Example 23 200 mg of 17a-ethynyl-3-cyclopentyloxy-17e-hydroxy-l,3,4(10)-oestratriene are dissolved in 2 ml of dry collidine, and, while cooling with ice and under nitrogen, 100 mg of 4-dimethylamino-pyridine and 650 mg of O-undecanoyl-glycolloyl chloride are added and the whole is heated for 3 hours at 70°C. After cooling, 122 mg of 4-dimethylami no-pyridine are added, and then a further 1 ml of collidine and 650 mg of the acid chloride are added. The mixture is again heated for 12 hours at 80°C. After cooling, taking up in ether and washing neutral with aqueous oxalic acid solution and water are carried out. After drying and concentrating, - 29 44330 the oily residue is chromatographed over silica gel. 95 mg of 17a-ethynyl3-cyclopentyloxy-17β-(O-undecanoylglycol! oyloxy )-1,3,5(10)-oestratriene are obtained in the form of a colourless oil.

Example 24 250 mg of 17a-ethynyl-17g-hydroxy-3-(propan-2-sulphonyloxy)-l,3,5(10)oestratriene are dissolved in 2.5 ml of dry collidine, and, while cooling v;i th ice and under nitrogen, 125 mg of 4-dimethyl ami no-pyridine and 900 mg of 0-valeryl-glycolloyl chloride are added. The mixture is heated for 6 hours at 90°C, and, after cooling, taking up in ether is carried out. After washing and drying, the ethereal phase is concentrated and the oily residue is chromatographed over silica gel. 190 mg of 17a - ethynyl 3 - (isopropyl sul phonyl oxy) - 17β -(0- valeryl - glycol loyl oxy) - 1,3,5(10) - oestratriene are obtained.

Example 25 100 mg of 17a-ethynyl-17(j-glycolloyloxy-4-oestren-3-one are dissolved in 1 ml of a mixture of benzene and triethylamine. While stirring, there is added to this solution at room temperature 0.15 ml of isopropyl sulphonyl chloride. The reaction mixture is allowed to stand for 16 hours, poured onto ice and, after decomposition of the excess of acid chloride, taking up in ether is carried out. The mixture is washed neutral, concentrated in vacuo, and the residue is taken up in benzene and filtered over silica gel. 120 mg of I7a-ethynyl-17g-(0-isopropylsulphonylglycolloyloxy)-4-oestren-3-one are obtained.

Example 26 500 mg of 17a-ethynyl-17g-hydroxy-4-androsten-3-one are dissolved in - 30 5 ml of collidine and reacted with O-undecanoyl-glycolloyl chloride in the manner analogous to that in Example 23. 370 mg of 17a-ethyny1-17g(0-undecanoyl-glycolloyloxy)-4-androsten-3-one are obtained.

Example 27 250 mg of 3p-acetoxy-17a-ethynyl-17g-hydroxy-4-oestrene are dissolved in 2.5 ml of dry collidine and reacted with O-undecanoyl-glycolloyl chloride in a manner analogous to that in Example 23. 160 mg of 3g-acetoxy-17aethynyl-17g-(0-undecanoyl-glycol1oyloxy)-4-oestrene are obtai ned.

Example 28 500 mg of 17g-(0-acetyl-glycolloyloxy)-17a-ethynyl-4-oestren-3-one are dissolved in 15 ml of dioxan. 1 ml of ortho-formic acid ethyl ester and 1.2 grams of para-toluene sulphonic acid are added and the whole is stirred for 6 hours at room temperature. 0.5 ml of pyridine is then added, and the product is precipitated in ice-water and filtered off with suction. The crude product is dissolved in benzene and filtered over a small amount of silica gel. The dienol ether (3-ethoxy-3,5-diene) so obtained is introduced into a boiling solution of 50 ml of benzene, 0.5 ml of cyclopentanol and 10 mg of para-toluene sulphonic acid. In the course of 30 minutes 5 ml of the solution are distilled off, and 0.15 ml of pyridine is added to the hot solution. After cooling, concentration in vacuo is carried out, the residue is taken up in methylene chloride, a small amount of methanol is added and the mixture is concentrated in vacuo. 125 mg of 17g -(0- acetyl - glycolloyloxy) - 17a - ethynyl - 3 - cyclopentyloxy 3,5 - oestradiene melting at 143—156°C are obtained.

Example 29 500 mg of 17a-ethynyl-17e-hydroxy-18-ethyl-4-oestren-3-one are introduced under nitrogen into a solution of 1 gram of 3-(methoxyundecandioyloxy)-propionic acid and 310 mg of trifluoracetic anhydride in 10 ml of benzene. After being allowed to stand for 24 hours at room temperature, ml of methanol is added to the solution, and it is concentrated in vacuo. By chromatography over silica gel there are obtained 280 mg of 17«-ethynyl18-ethyl-178-{3-(methoxyundecandioyloxy)-propionyloxy}-4-oestren-3-one.

Example 30 500 mg of 17a-ethyny1-17β-hydroxy-l8-methyl-15a,16a-ffiethylene-4oestren-3-one are reacted with crotonic acid and the product further reacted in a manner analogous to that in Example 1. 250 mg of 170-(0propionyl-glycolloy1oxy)-l7a-ethynyl-l8-methyl-l5a,l6a-methylene-4-oestren3-one are obtained.

Example 31 500 mg of 17a-ethynyl-17g-hydroxy-18-methyl-158,168-methylene-4oestren-3-one are reacted with crotonic acid and the product further reacted as described in Example 1. 370 mg of 178-(0-propionyl-glycolloyloxy)17a-ethynyl-18-methyl-15β,1δβ-methylene-4-oestren-3-one are obtai ned.

Example 32 725 mg of 4-acetoxybutyric acid are dissolved in 20 ml of benzene, and 5 ml of benzene are distilled off. After the addition of 1.1 gram of trifluoracetic anhydride, the mixture is stirred for one hour at room temperature. 1 Gram of 4,6-dichloro-l7-hydroxy-1a,2a-methylene-4,6-pregna- 32 4 4 3 2 0 dien-3,20-dione is added under nitrogen, and the whole is stirred for 36 hours at room temperature. The reaction solution is decomposed with methanol and concentrated in vacuo. The residue is chromatographed over silica gel. 470 mg of 17-(4-acetoxybutyryloxy)-4,6-dichloro-la,2a-methylene4,6-pregnadiene-3,20-dione are obtained.

Example 33 250 mg of 17a-ethynyl-17g-hydroxy-4,9(10),ll(12)-oestratrien-3-one are reacted with 3-acetoxy-propionic acid in a manner analogous to that in Example 7. 110 mg of 17g -(3- acetoxypropionyloxy) - 17a - ethynyl 4,9(10),11(12) - oestratrien - 3 - one are obtained.

Example 34 To a solution of 500 mg of 17-hydroxy-6a-methyl-4-pregnene-3,20-dione in 5 ml of dry methylene chloride is added under nitrogen a freshly prepared solution of 435 mg of acetoxyglycollic anhydride in dry ether. After the addition of 5 μ litres of perchloric acid of 60% strength, the whole is allowed to stand for 24 hours, the reaction solution is decomposed with methanol and concentrated at room temperature in vacuo, in order to avoid splitting the undesired 3-enol-compound present in the mixture. The residue is chromatographed over silica gel. 17-(0-acety1-glycolloyloxy)6a-methy1-4-pregnene-3,20-dione is obtained.

Example 35 To 20 ml of benzene are added 530 mg of 3-acetoxy-propionic acid, and 5 ml of the benzene are distilled off. 770 mg of trifluoracetic anhydride are then added and the whole is allowed to stand at room temperature for 1 hour. While gassing with nitrogen 1 gram of 6-chloro-17-hydroxyla,2a-methylene-4,6-pregnadiene-3,20-dione is added. The mixture is allowed - 33 44320 to stand for 36 hours at room temperature, decomposed v/ith methanol, washed with sodium hydrogen carbonate solution and concentrated in vacuo.

The residue is dissolved in 5 ml of methylene chloride and 5 ml of methanol, an ethanolic solution of potassium hydroxide is added and the mixture is allowed to stand under nitrogen for 3 hours at +5°C. After acidification v/ith acetic acid, ether is added and the mixture is washed neutral. After drying and concentrating, the residue is chromatographed over silica gel. 430 mg of 17-(3-acetoxy-propionyloxy)-6-chloro-la,2a-methylene-4,6-pregnadiene-3,20-dione melting at 196—198°C. (from ethyl acetate) are obtained.

UV: ε283 = 16900.

Example 36 375 mg of thiodiglycollic acid are suspended in 20 ml of benzene and 500 mg of trif1uoracetic anhydride are added. After stirring for one hour, 400 mg of 4,6-dichloro-17-hydroxy-4,6-pregnadiene-3,20-dione are added, and the whole is allowed to stand for 24 hours at room temperature. The mixture is then stirred into ice-water, adjusted to a pH-value of 8 with sodium hydroxide solution, and the mixture is extracted with ether. The aqueous phase is then acidified with 2N sulphuric acid, the precipitated product is brought into solution with methanol and heated for one hour under reflux. After cooling, the methanol is removed in vacuo and the precipitated product is filtered off with suction. It is washed with water until the thiodiglycollic acid is removed. It is dried in vacuo, and 260 mg of 17-(carboxymethylthioacetoxy)-4,6-dich1oro-4,6-pregnadiene-3,20-dione are obtained.

Example 37 500 mg of 17a-ethynyl-17g-hydroxy-4-oestren-3-one are dissolved in 5 ml - 34 4 4 3 2 0 of dry collidine, and, while cooling with ice and gassing with nitrogen, 800 mg of α-acetoxy-isobutyryl chloride are added. The mixture is heated for 3 hours at 70°C, cooled, a further 2 ml of collidine is added, and 180 mg of 4-dimethylamino-pyridine and a further 0.8 gram of acid chloride are added. After further heating at 70°C for 16 hours, the mixture is cooled, and worked up in a manner analogous to that in Example 9. 270 mg of 17β-(0-acetyldimethylglycol1oyloxy)-17a-ethynyl-4-oestren-3-one are obtained.

Example 38 mg of 17-(carboxymethylthio-acetoxy)-4,6-dichloro-4,6-pregnadiene3,20-dione are dissolved in 5 ml of ether/tetrahydrofuran mixture, and an ethereal solution of diazomethane is added. The mixture is allowed to stand for one hour, then concentrated and chromatographed over silica gel. mg of 4,6-dichloro-17-(methoxycarbonylmethylthioacetoxy)-4,6-pregnadiene3,20-dione are obtained.

Example 39 An oily solution for intramuscular injection having a long lasting action The injection solution is compounded by the usual methods under sterile conditions from the following constituents: 5000 mg of 17a-ethynyl-18-methyl-17g-(0-undecanoyl-glycolloyloxy)-4oestren-3-one are dissolved in a mixture of castor oil/benzyl benzoate (6:4) and made up to 100 ml. The solution is charged in quantities of 1 ml into ampoules, of which each contains 50 mg of active substance.

Example 40 A crystal suspension for intramuscular injection having a long lasting action The suspension is prepared by known methods and sterilised. 2000 mg of 17a-ethynyl-17e-(0-heptanoylglycolloyloxy)-18-methyl-4oestren-3-one having a particle size smaller than 20 pm are suspended in a physiological solution of sodium chloride, which contains 85 mg of Hyrj 53 (Trade Hark) and made up to 100 ml. The suspension is charged in quantities of 1 ml into ampoules and sterilised. Each ampoule contains 20 mg of active substance.

Claims

1. An ester of a pharmacologically active 17-hydroxy steroid having an unsubstituted alkynyl or chlorine-substituted alkynyl radical in the 17a-position or an unsubstituted acetyl or fluorine-substituted acetyl radical in the 17g-position, with an acid of the general formula Z—COOH wherein Z represents X—OH, X—0—CO—Y—CO—OH, X—0—CO—R, X—0—CO—Y—CO—OR or X—S—S0 2 —R in which X represents a saturated bivalent hydrocarbon radical having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and may be unsubstituted or substituted by one or more of the same or different substituents selected from —OH, —OCOR and —0S0 z R groups, Y represents a direct bond, a bivalent aliphatic radical which may be uninterrupted or interrupted by one or more of the same or different atoms selected from oxygen and sulphur, and which has from 1 to 16 carbon atoms, or a cyclohexylene, cyclopentylene or phenylene group which may be unsubstituted or substituted by one or more of the same or different substituents selected from methyl and ethyl groups, and R represents a hydrocarbon or heterocyclic radical which may be unsubstituted or substituted and which has in total up to 22 carbon atoms. - 37 44330

2. A depot-steroid ester of the general formula in which each of the rings A, B, C and 0 may be unsubstituted or substituted, and may be saturated or unsaturated, 5 R 10 represents a hydrogen atom or a methyl group, R 13 represents an alkyl group containing 1 to 3 carbon atoms, R 17 represents an alkynyl group in the 17a-position or an acetyl group in the 17g-position, Z represents a group of the general formula X—OH, 10 X—0—CO—Y—-CO—OH, X—0—CO—R, X—0—CO—Y—CO—OR or X—0—S0 2 —R, in which X represents a straight or branched alkylene group having from 1 to 6 carbon atoms which may be uninterrupted or interrupted by one or more oxygen or sulphur atoms, and may, if desired, be 15 substituted by —OH, —OCOR or —SO 2 R, Y represents a direct bond, a straight or branched carbon chain which has 1 to 16 carbon atoms and may be uninterrupted or inter- 38 44320 rupted by one or more oxygen or sulphur atoms, or a 1,2-, 1,3or 1,4-phenylene, 1,2-, 1,3- or 1,4- cyclohexylene or 1,2- or 1,3-cyclopentylene group which is unsubstituted or substituted by a methyl or ethyl group, and the or each 5 R represents an unsubstituted or substituted hydrocarbon or hetero cyclic radical containing up to 22 carbon atoms.

3. An ester as claimed in claim 2, wherein the rings A, B, C and D are unsubstituted or substituted by one or more substituents selected from etherified and esterified hydroxyl groups in the 1-, 2-, 3-, 4-, 7-, 10 11-, 15- and 16-positions, keto groups in the 3-, 6- and 11-positions, aliphatic groups having up to 5 carbon atoms in the 1-, 2-, 4-, 6-, 7and 16-positions, methylene groups in the 1,2-, 6,7- and 15,16-positions and halogen atoms in the 2-, 4-, 6-, 7-, 9-, 11- and 16-positions, and are saturated or contain a double bond in one or more positions selected from 15 the 1(2)-, 3(4)-, 4(5)-, 5(10)-, 5(6)-, 6(7)-, 9(10)-, 9(11)-, 11(12)and 15(16)-positions.

4. An ester as claimed in any one of claims 1 to 3, wherein the 17«substituent is ethynyl, chlorethynyl, propynyl or butadiynyl.

5. An ester as claimed in claim 4, wherein the 17a-substituent is 20 ethynyl.

6. An ester as claimed in claim 2, which has the general formula - 39 in which R 13 and Z have the meanings given in claim 2, the broken lines represent optional further carbon-to-carbon bonds, A represents, together with adjacent carbon atoms of the B ring, the grouping R 3 0 and the C ring contains a double bond in the 11,12-position, or the grouping R 3 0 Rio Rio and the C ring is saturated, R 10 represents a hydrogen atom or a methyl group, R 3 represents a hydrogen atom, a (Οχ—C s )-acyl, (Οχ—C 6 )-a1kylsulphonyl, (Οχ—C 6 )-alkyl or (03—C 8 )-cycloalkyl group. W = H z , 0 or H, 0R 3 represents a double bond in the 4,5-, 5,6- or 5,10-position and Ri 5 and R 15 each represents a hydrogen atom or both together represent a methylene group in the a- or B-position or a further carbon-to- 40 carbon bond between the carbon atoms C 15 and C 16 .

7. An ester as claimed in claim 2, which has the general formula in which R 1(i , R J3 and Z have the meanings given in claim 2, 5 Ri and R 2 each represents a hydrogen atom or both together represent a methylene group or a further carbon-to-carbon bond between the carbon atoms Cj and C 2 , R u represents a hydrogen or a chlorine atom, R 6 represents a hydrogen or chlorine atom or a methyl group, and 10 6—7 represents a single or double bond between the carbon atoms C 5 and C 7 .

8. An ester as claimed in any one of claims 1 to 7, wherein the radical represented by R is substituted by one or more substituents, any two or more of which may be the same or different, selected from oxo and amino 15 groups and halogen atoms, and/or in the case of a hydrocarbon group is interrupted by one or more oxygen atoms.

9. An ester as claimed in any one of claims 1 to 8, wherein the radical - 41 44330 represented by R has from 4 to 18 carbon atoms.

10. An ester as claimed in any one of claims 1 to 9, wherein the alkylene radical represented by X has from 1 to 3 carbon atoms.

11. A salt of a compound claimed in any one of claims 1 to 10.

12. A physiologically tolerable salt of a compound claimed in any one of claims 1 to 10.

13. 17a-Ethynyl-18-methyl-17β-(O-propi onyl-glycol1oyloxy)-4-oestren3-one.

14. 17a-Ethynyl-l7p-(0-heptanoyl-glycolloyloxy )-18-methyl-4-oestren3-one.

15. 17a-Ethynyl-18-methyl-17β-(O-undecanoyl-glycol1oyloxy)-4-oestren3-one.

16. 17a-Ethynyl-17g-glycol1oyloxy-18-methyl-4-oestren-3-one.

17. 17a - Ethynyl - 17β - {0 - (3 - cycl opentyl propionyl) *· glycolloyloxyl - 18 - methyl - 4 - oestren - 3 - one.

18. 17a-Ethyny1-17b-(2-nonanoyloxy-propi onyloxy)-18-methyl-4-oestren3-one.

19. -17p-(3-Acetoxy-propionyloxy)-l7a-ethynyl-18-methyl-4-oestren-3one.

20. 17a-Ethynyl-17β-(3-hydroxy-propi onyloxy-18-methyl-4-oestren-3one.

21. 17a - Ethynyl - 17β -(0-10- methyl - 3,6,9 - tri oxaundecanoyl glycolloyloxy) - 4 - oestren - 3 - one.

22. 17 β-(Ο-Acetyl-glycol 1oyloxy)-17a-ethyny1-4-oestren-3-one.

23. 17a-Ethynyl-l7g-glycol1oyloxy-4-oestren-3-one. - 42 ; ΊΟ

24. 17λ - Ethynyl -17---(0-(4- octyloxy - benzoyl) - benzoyl) glycolloyloxy} - 4 - oestren - 3 - one.

25. 17a - Ethynyl - 17β -(0-(4- octyl oxycarbonyl - cyclohexylcarbonyl) - glycolloyloxy} - 4 - oestren - 3 - one.

26. 17a - Ethynyl - 17β -(0- methoxycarbonylmethyl - glycolloyloxy) 4 - oestren - 3 - one.

27. 17a - Ethynyl - 17β - (0 - decycloxycarbonylmethyl - glycolloyloxy) - 4 - oestren - 3 - one.

28. 17a-Ethynyl - 17p-(4-undecanoyloxy-cyclohexylcarbonyloxy)-4oestren-3-one.

29. 17β-(Ο-Acetyl-glycol1oyloxy)-17a-ethynyl-4-oestrene.

30. 17a-Ethynyl-17 β-glycol1oyloxy-4-oestrene.

31. 17a-Ethynyl-17B-(0-stearoyl-glycolloyloxy)-4-oestrene.

32. 17a - Ethynyl - 17β -(0- undecanoyl - glycolloyloxy) - 5(10) oestren - 3 - one.

33. 17a-Ethynyl-17β-(0-undecanoyloxy-glycol1oyloxy)-4-oestren-3-one.

34. 17β -(0- Acetyl - glycolloyloxy) - 17a - ethynyl - 3 - methoxy 1,3,5(10) - oestratriene.

35. 17a-Ethynyl-17B-glycolloyloxy-3-methoxy-l,3,5,(10)-oestratriene.

36. 17a - Ethynyl - 17g -(0- isovaleryl - glycolloyloxy) - 3 methoxy - 1,3,5(10) - oestratriene.

37. 17a - Ethynyl - 17β -(0- undecanoyl - glycolloyloxy) - 1,3,5(10)oestratrien - 3 - ol.

38. 17a - Ethynyl - 3 - cyclopentyloxy - 17β - (0 - undecanoyl) glycolloyloxy) - 1,3,5(10) - oestratriene. - 43 44320

39. 17 α - Ethynyl - 3 - (isopropyl - sulphonyloxy) - 17g -(0- valeryl glycolloyloxy) - 1,3,5(10) - oestratriene.

40. 17a-Ethynyl-17e-(0-isopropyl-sulphonyl-glycolloyloxy)-4-oestren3-one.

41. 17a-Ethynyl-17p-(O-undecanoyl-glycol1oyloxy)-4-androsten-3-one.

42. 3g-Acetoxy-l7 a -ethynyl-17ρ-(0-undecanoyl-glycol1oyloxy)-4-oestrene.

43. 17p-(Ο-Acetyl-glycol1oyloxy)-17a-ethynyl-3-cyclopentyloxy-3,5oestradiene.

44. 17 a - Ethynyl - 18 - ethyl - 17β - {3 - (methoxyundecandioyloxy) propionyloxy) - 4 - oestren - 3 - one.

45. 17g -(0- Propionyl - glycolloyloxy) - 17 a - ethynyl - 18 methyl - 15 a ,16 u - methylene - 4 - oestren - 3 - one.

46. 17ρ -(0- Propionyl - glycolloyloxy) - 17a - ethynyl - 18 methyl - 15β,16β - methylene - 4 - oestren - 3 - one.

47. 17 -(4- Acetoxy - butyryloxy) - 4,6 - dichloro - la,2a methylene - 4,6 - pregnadiene - 3,20 - dione.

48. 17β - (3 - Acetoxy - propionyloxy) - 17a - ethynyl - 4,9(10),11(12) oestratrien - 3 - one.

49. 17-(O-Acetyl-glycol1oyloxy)-6a-methyl-4-pregnene-3,20-dione.

50. 17-(3- Acetoxy - propionyloxy) - 6 - chloro - la,2a - methylene4,6 - pregnadiene - 3,20 - dione.

51. 17-(Carboxymethylthi o-acetoxy)-4,6-di chioro-4,6-pregnadi ene3,20-dione.

52. 17B-(0-Acetyl-dimethylglycolloyloxy)-17a-ethyny1-4-oestren-3~one.

53. 4,6 - Dichloro - 17 - (methoxy - carbonylmethylthio - acetoxy) 4,6 - pregnadiene - 3,20 - dione. - 44 4433ο

54. 17a-Ethynyl-17g-(0-tridecanoly-glycoll oyloxy)-4-oestren-3-one.

55. 17a-Ethyn.yl -17β- (O-hexadecanoyl -glycol 1 oyl oxy) -4-oestren-3-one.

56. 17a-Ethynyl-17s-(O-octadecanoyl-g1ycol1oyloxy)-4-oes tren-3-one.

57. 17a-Ethynyl-17β-(0-tridecanoyl-glycol1oyloxy)-18-methyl-4-oastren5 3-one.

58. 17a - Ethynyl - 17β -(0- tridecanoyl - glycolloyloxy) - 18 methyl - 4,15 - oestradien - 3 - one.

59. 17a - Ethynyl - 3,3 - (2,2 - dimethyl - trimethylenedioxy) - 17gglycolloyloxy - 18 - methyl - 5 - or 5(10)oestrene. 10

60. A process for the preparation of an ester as claimed in claim 1 or a salt thereof, which comprises esterifying the 17-hydroxy group in a pharmacologically active 17-hydroxy steroid having an unsubstituted alkynyl or chlorine-substituted alkynyl radical in the 17a-position or an unsubstituted acetyl or fluorine-substituted acetyl radical in the 17B-position. 15

61. A process for the preparation of an ester as claimed in claim 2, or a salt thereof, which comprises esterifying a steroid alcohol of the general formula in which A, B, C, D, R lo , R 13 and R 17 are as specified in claim 2. - 45 44320

62. A process for the preparation of an ester as claimed in claim 2, which has the general formula O-C-CH 2 OH (la) which comprises reacting an alcohol of the general formula IV specified 5 in claim 61 with crotonic acid in the presence of trifluoroacetic anhydride to form the 17-crotonic acid ester, protecting any keto group present, oxidising the ester with potassium permanganate in the presence of formic acid to form the 2,3-dihydroxy-butyric acid ester, oxidatively splitting with periodate at a temperature of from 0 to 50°C to form the 17-glyoxalic 10 acid ester, reducing the 17-glyoxalic acid ester with an alkali metal boranate or lithium tri-tert.-butoxy alanate to form the 17-glycollic acid ester and liberating any protected keto groups present.

63. A process as claimed in claim 60, carried out substantially as described herein. 15

64. A process as claimed in claim 60, carried out substantially as described in any one of the Examples 1 to 38 herein.

65. An ester as claimed in claim 1, whenever prepared by a process as claimed in any one of claims 60 to 64, - 46 44320

66. A salt of a compound claimed in claim 1, whenever prepared by a process as claimed in any one of claims 60 to 64.

67. A physiologically tolerable salt of a compound claimed in claim 1, whenever prepared by a process as claimed in any one of claims 60 to 5 64.

68. A pharmaceutical preparation which comprises a compound claimed in any one of claims 1 to 10, 12 to 59, 65 and 67, in admixture or conjunction with a pharmaceutically suitable carrier.

69. A pharmaceutical oreparation as claimed in claim 68, which is in 10 dosage unit form.

70. A pharmaceutical preparation as claimed in claim 68 or claim 69, which is in oily solution or in aqueous crystalline suspension and is in 1 to 4 ml ampoules suitable for injection.

71. A pharmaceutical preparation as claimed in claim 71, which is in 15 1 to 2 ml ampoules.

72. A pharmaceutical preparation as claimed in claim 68, which is substantially as described in Example 39 or Example 40 herein.